The majority of breast cancer patients die of cancer metastasis rather than primary tumor growth. However, we know very little about the mechanisms and the gene networks responsible for regulation of breast cancer metastasis due to the lack of appropriate animal models and the difficulties to identify metastasis-specific genes. Recently, we and others observed that the steroid receptor coactivator-1 (SRC-1) is overexpressed in metastatic human cancers, suggesting it may play an important role in breast cancer metastasis. To study the role of SRC-1 in mammary gland development and tumorigenesis, we have generated SRC-1 knockout mice. We showed that inactivation of SRC-1 in mice drastically suppresses oncogene-induced breast cancer metastasis without affecting the primary breast tumor formation and growth. Transplantation analysis further revealed that the suppression of mammary tumor metastasis is accredited to the autonomous function of SRC-1 in the mammary tumor cells. These findings clearly indicate that SRC-1 is a novel key regulator of the breast cancer metastasis. This project will characterize the specific contribution and regulatory mechanism of SRC-1 in breast cancer metastasis. First, we will generate transgenic mice with mammary epithelial cell-specific overexpression of SRC-1 to address whether SRC-1 overexrpession promotes oncogene-induced breast cancer metastasis in vivo. We also will investigate whether overexpression of SRC-1 in non-metastatic human breast cancer cells will enhance their motility and invasive behavior in culture and change these non-metastatic cells into metastatic cells in nude mice. Second, we plan to study SRC-1 as a target for inhibiting breast cancer metastasis by examining whether knockdown of SRC-1 in metastatic human breast cancer cells will blockade or reduce their metastasis capability. Third, we will investigate the roles of several SRC-1-regulated genes in breast cancer metastasis. Finally, we will try to understand the regulatory mechanisms by which SRC-1 regulates its target genes relevant to breast cancer metastasis. These SRC-1 target genes were identified by gene array analysis. We believe that these carefully designed studies will provide a new avenue of research to understand certain essential aspects of breast cancer metastasis and lead to identification of new molecular markers and drugable targets for better diagnosis, prognosis and treatment of breast cancer metastasis. [unreadable] [unreadable]